PROJECT SUMMARY Unnecessary Clostridium difficile testing is pervasive across many hospitals in the United States. Up to 50% of hospitalized patients diagnosed and treated for Clostridium difficile infection (CDI) may not have true CDI. This is due to four interrelated factors: 1) C. difficile colonization of the colon is common in hospitalized patients, 2) widely used C. difficile nucleic acid amplification testing (NAAT) diagnostic tests detect presence of C. difficile toxin gene, but a positive test does not necessarily indicate toxin production or active infection, 3) hospitalized patients frequently have diarrhea for a variety of reasons, and 4) unnecessary testing occurs frequently in cases of low CDI pre-test probability. Colonized patients, misclassified as infected, receive unnecessary antibiotics that disrupt the colon microbiome, which may increase risk for subsequent C. difficile infection, acquisition of multidrug resistant organisms. Unnecessary testing artificially inflates publicly reported rates of Laboratory- identified Clostridium difficile events, a Centers for Disease Control and Prevention National Healthcare Safety Network patient safety metric. The overall goal of this study is to optimally reduce unnecessary C. difficile testing at ten acute care hospitals, using a diagnostic stewardship intervention package enhanced by human factors engineering (HFE) and cultural anthropological approaches. We will implement and disseminate an electronic medical record clinical decision support tool across participating hospitals and will incorporate novel data feedback strategies to enhance uptake of the intervention. This work will be informed by the Systems Engineering Initiative for Patient Safety (SEIPS) Model, which frames the design of the work system elements (e.g., people, physical environment, task, organization, tools/ technologies) and how their interactions influence the process of C. difficile test ordering. We will conduct debriefs, semi-structured interviews and focus groups with front line healthcare workers to identify the major issues that lead to unnecessary testing and non-compliance with electronic medical record clinical decision support tools. Successful completion of the proposed research will have a major, direct impact on reducing inappropriate C. difficile testing in acute care settings, decrease unnecessary antibiotic use, and inform a novel toolkit that could be adapted for future diagnostic stewardship intervention.